The creation and development of non-natural oligomeric peptide mimics, or so called peptidomimetics, hasbecome an area of high interest in bioorganic and chemical biology. These peptidomimetics are designed tomimic peptide primary structure through the use of unnatural backbones. They are often stable against proteolysis,and are believed to have reduced immunogenicity and improved bioavailability compared to peptides. Nonetheless, the applications of peptidomimetics are still very limited, partially hampered by the availability offrameworks. A wide range of new peptide mimics with new structures and functions are urgently needed to beexplored. Recently, we have developed a new class of peptidomimetics termed ?-AApeptides. Such peptidemimics are highly resistant to proteases and easily amendable to derivatize with limitless potential. Our longtermgoal is to develop ?-AApeptides that can mimic the structure and function of bioactive peptides, so as todevelop potential agents for therapeutic purpose or used as probes to investigate or modulate important biologicalprocesses. The objective here, which is our next step in pursuit of that goal, is to identify ?-AApeptidesthat can mimic the global structure, function and mechanism of action of antimicrobial peptides (AMPs). Ourcentral hypothesis is that ?-AApeptides, with proper structural similarity to bioactive peptides, are able to mimicthe function of those peptides. Our specific aims are 1. Identify potent lipo-cyclic ?-AApeptides that are activeagainst both Gram-positive MRSA (MIC ? 2 ?g/ml) and Gram-negative P. aeruginosa (MIC ? 3?g/mL). Built upon our preliminary studies, our working hypothesis is that by mimicking the globally amphipathicstructure of AMPs, ?-AApeptides are able to mimic the function of AMPs, and will be active with broadspectrumactivity. As such, the potent antimicrobial ?-AApeptides which are active against both drug-resistantGram-positive and Gram-negative bacteria can be designed, synthesized and identified. 2. Confirm that bactericidalmechanism of lipo-cyclic ?-AApeptides involves bacterial membrane disruption. Again basedon our preliminary data, we hypothesize that when ?-AApeptides form globally cationic amphipathic structures,they can mimic the mechanism of AMPs by killing bacterial pathogens through disruption of bacterial membranes. 3. Evaluate the in vivo activity of lipo-cyclic ?-AApeptides against Methicillin-resistant Staphylococcusaureus (MRSA) in a mouse model. Based on our preliminary data, we will use a mouse thigh infectionmodel to evaluate the antimicrobial activity of lead lipo-cyclic ?-AApeptides in vivo. The work proposed inthe aims above will identify potent antimicrobial ?-AApeptides that mimic global structure and mechanism ofaction of AMPs. Therefore, it will lead to a new generation of antibiotics to treat drug-resistant bacterial pathogens.In addition, the research wil demonstrate the biological potential of?-AApeptides, and lead to new biomedicalapplications of ?-AApeptides in the future through mimicry of bioactive peptides, i.e., mimicry of amphiphiliclung surfactants and agricultural pesticides, etc.